ABSTRACT This proposal is submitted in response to PAR-15-356: Major Opportunities for Research in Epidemiology of Alzheimer's Disease and Cognitive Resilience. This study will examine the relation of the pathologies of AD and related disorders in brain, brainstem and spinal cord associated with body sensor gait measures. Then we will construct and validate a gait biomarker for AD pathology. The pathology of Alzheimer's disease (AD) begins years prior to the onset of overt cognitive impairment. This proposal builds on work by our group and others suggesting that AD pathology may cause impaired gait years before AD dementia. A recent NIH workshop concluded that the development of a gait biomarker relatively specific for AD pathology may identify older adults at risk for AD dementia and could facilitate early treatments that prevent dementia. Key knowledge gaps impede the construction of a gait biomarker. First, conventional gait measures are not specific for AD pathology. Second, current indices of brain pathologies of AD and related disorders account for only a small proportion of the variance in gait suggesting that other brain pathologies remain to be identified. Third, prior autopsy studies have focused on the brain, so it is unknown if pathologies of AD and related disorders in brainstem and spinal cord are associated with gait. This proposal is supported by compelling preliminary work. We show that: 1) the pathologies of AD and related disorders accumulate in brainstem and spinal cord and are associated with gait in older adults. 2) Postmortem brain MRI indices of microvascular tissue alterations and activated CNS microglia are related to gait. 3) Body sensor gait metrics which assess more dimensions of mobility than conventional gait speed are related to late-life cognitive impairment. This study leverages data and participants in the Memory and Aging Project (MAP, R01AG17917), an ongoing clinical-pathologic study of AD, all of whom donate brain and spinal cord at death. To fill key knowledge gaps, we propose to collect and quantify annual body sensor gait metrics. In decedents, we will quantify pathologies of AD and related disorders and activated microglia in brain, brainstem and spinal cord and extract indices of postmortem brain MRI to determine the pathologic basis of impaired gait in older adults (Aim 1& 2). Then we will construct a body sensor gait biomarker relatively specific for AD pathology by controlling for non-AD pathologies and activated microglia (Aim 3). Then in an independent group of MAP participants, we will validate the gait biomarker by showing that it predicts cognitive decline and AD dementia (Aim 4). This biomarker has potential to facilitate early treatments that prevent AD dementia in millions of older Americans.